The c-Jun NH2-terminal kinase (JNK) is a member of the stress-activated group of Mitogen Activated Protein kinases (MAP kinases) implicated in the control of cell growth. The JNK signal transduction pathway is activated in response to environmental stress and by the engagement of several classes of cell surface receptors, including cytokine receptors, serpentine receptors, and receptor tyrosine kinases. Whitmarsh et al., J. Mol. Med., 74:589 (1996). In addition, genetic studies of Drosophila have demonstrated that JNK is required for early embryonic development. Sluss et al., Genes & Dev., 10:2745 (1996); Riesgo-Escovar et al., Genes & Dev. 10:2759 (1996). In mammalian cells, JNK has been implicated in the immune response, oncogenic transformation, and apoptosis. JNK mediates these effects, at least in part, by increasing the expression of target genes. Targets of the JNK signal transduction pathway include the transcription factors c-Jun, ATF2, and Elk-1. Whitmarsh et al., supra.
JNK is activated in the liver by metabolic oxidative stress. Mendelson et al., Proc. Natl. Acad. Sci. USA 93:12908-12913 (1996). Activation of JNK also occurs in the kidney during stress, for example, during Bchemic renal failure. Demari et al., Am. J. Physiol. 272:F292-F298 (1997). JNK is also activated during cardiovascular disease such as ischemia Ireperfusion and during organ transplantation. Pombo et al., J. Biol. Chem. 269:26546-26551 (1994); Force et al., Circ. Res. 78:947-53 (1996).
While JNK is located in both the cytoplasmic and the nuclear compartments of quiescent cells, activation of the JNK signal transduction pathway is associated with accumulation of JNK in the nucleus. Mechanisms governing this sub-cellular distribution have not been previously elucidated.
Anchor or tethering proteins play an important role in the regulation of multiple signal transduction pathways. These anchor proteins, which include the nuclear factor kappa B (NFkB) inhibitor IkB, the A kinase anchor protein (AKAP) group of proteins that bind the type II cyclic adenosine monophosphate (AMP) dependent protein kinase, and the p190 protein that binds Ca2+-calmodulin-dependent protein kinase II, localize their tethered partners to specific sub-cellular compartments. Verma et al., Genes & Dev., 9:2723 (1995); McNeill et al., J. Biol. Chem., 270:10043 (1995); Faux et al., Trends Biochem. Sci., 21:312 (1996)). Anchor proteins also target enzymes to specific substrates, and create multi-enzyme signaling complexes, such as the Ste5 MAP kinase scaffold complex and the AKAP79 kinase/phosphatase scaffold complex. Choi et al., Cell, 78:499 (1994); Klauck et al., Science, 271:1589 (1996); Faux et al., Cell, 85:9 (1996)).